Deletion of the hypoxia-response element in the vascular endothelial growth factor promoter causes motor neuron degeneration
Abstract
Hypoxia stimulates angiogenesis through the binding of hypoxia-inducible factors to the hypoxia-response element in the vascular endothelial growth factor (Vegf) promotor. Here, we report that deletion of the hypoxia-response element in the Vegf promotor reduced hypoxic Vegf expression in the spinal cord and caused adult-onset progressive motor neuron degeneration, reminiscent of amyotrophic lateral sclerosis. The neurodegeneration seemed to be due to reduced neural vascular perfusion. In addition, Vegf165 promoted survival of motor neurons during hypoxia through binding to Vegf receptor 2 and neuropilin 1. Acute ischemia is known to cause nonselective neuronal death. Our results indicate that chronic vascular insufficiency and, possibly, insufficient Vegf-dependent neuroprotection lead to the select degeneration of motor neurons.
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The ERN1 and CAPG genes might also be involved in the innate immune response since hypoxia triggers innate immunity responses through the activation of HIF-1α.
“The ERN1 and CAPG genes might also be involved in the innate immune response since hypoxia triggers innate immunity responses through the activation of the hypoxia induced factor α1 (HIF-1α) (Oosthuyse et al., 2001; Rius et al., 2008; Singh et al., 2016).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Oosthuyse et al., 2001
Reduction of the hypoxic response element in the spinal cord results in the progressive degradation of the motor neuron.
“The reduction of the hypoxic response element in the spinal cord results in the progressive degradation of the motor neuron (Oosthuyse et al., 2001; Minchenko et al., 2015).”
From Identification of Candidate Signature Genes and Key Regulators Associated With Trypanotolerance in the Sheko Breed (2019) · cites this paper as Oosthuyse et al., 2001
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References 48 · Cited by 1,007
- Authors
- Oosthuyse, B., Moons, L., Storkebaum, E., Beck, H., Nuyens, D., Brusselmans, K., Dorpe, J. V., Hellings, P., Gorselink, M., Heymans, S., Theilmeier, G., Dewerchin, M., Laudenbach, V., Vermylen, P., Raat, H., Acker, T., Vleminckx, V., Bosch, L. V. D., Cashman, N., Fujisawa, H., Drost, M. R., Sciot, R., Bruyninckx, F., Hicklin, D. J., Ince, C., Gressens, P., Lupu, F., Plate, K. H., Robberecht, W., Herbert, J.-M., Collen, D., & Carmeliet, P.
- Affiliations
- KU Leuven (BE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Maastricht University (NL)
- Inserm (FR)
- University of Amsterdam (NL)
- University of Toronto (CA)
- Nagoya University (JP)
- Thrombosis Research Institute (GB)
- Sanofi (France) (FR)
- Corresponding author
- Carmeliet, Peter
- ORCID
- Venue
- Nature Genetics
- Published
- 2001-06
- Volume
- 28
- Issue
- 2
- Pages
- 131-138
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W1894493322
- Cited by
- 1,007
- References
- 48
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 10 · 2023: 20 · 2022: 13 · 2021: 20 · 2020: 27 · 2019: 16 · 2018: 26 · 2017: 27 · 2016: 27 · 2015: 24 · 2014: 37 · 2013: 32 · 2012: 62
- FWCI
- 48.57
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Lirias (submittedVersion)
- VUBIR (Vrije Universiteit Brussel) (submittedVersion)
- Research Publications (Maastricht University) (submittedVersion)
- Funders
- Deutsche Forschungsgemeinschaft
- Fonds Wetenschappelijk Onderzoek
- Topics
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Angiogenesis and VEGF in Cancer
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- hypoxia response element, vascular endothelial growth factor, VEGF promoter, motor neuron degeneration, amyotrophic lateral sclerosis, hypoxia, angiogenesis, hypoxia-inducible factor, spinal cord, VEGF165, VEGFR2, neuropilin-1, neuroprotection, vascular insufficiency, acute ischemia
- MeSH terms
- Amyotrophic Lateral Sclerosis, Animals, Axons, Binding Sites, Electrophysiology, Humans, Lymphokines, Motor Neurons, Muscle Contraction, Muscular Atrophy, Nerve Degeneration, Nerve Tissue Proteins, Peripheral Nerves, Promoter Regions, Genetic, Spinal Cord, Cell Hypoxia, Endothelial Growth Factors, Sequence Deletion, Receptors, Growth Factor, Mice, Knockout, Muscle Fibers, Skeletal, Response Elements, Receptor Protein-Tyrosine Kinases, Neuropilin-1, Receptors, Vascular Endothelial Growth Factor, Vascular Endothelial Growth Factors, Vascular Endothelial Growth Factor A, Mice
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